Transdermal Therapeutic System for Administering an Active Substance

ABSTRACT

The present invention relates to a transdermal therapeutic system for administering an active substance through the skin, said system being suitable for an application period of at least three days, comprising the layers arranged in the following order with respect to each other:
         a) a cover layer,   b) an active substance layer comprising a polymer matrix containing the active substance,   c) an adhesive layer comprising a contact adhesive, which consists of a mixture of one or more polyisobutylenes and one or more polybutenes, and   d) a pull-off layer.

The object of the present application is a system for the transdermaladministration of an active substance, preferably rivastigmine, itsphysiologically compatible salt, hydrate, solvate, or derivative that issuitable for a therapeutic application period of several days.

Rivastigmine is the phenylcarbamate(S)—N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl-carbamate of theformula I.

It is a cholinesterase inhibitor acting in the central nervous systemand thus, is an active substance for the treatment of the Alzheimer'sdisease and Parkinson's dementia.

Rivastigmine may be present as a free base, but also as an acid additionsalt, hydrate, solvate, or as another derivative. These derivatives areencompassed in der present invention with the designation“rivastigmine”, unless otherwise described.

A preferred form to administer rivastigmine is the percutaneousadministration by means of a transdermal therapeutic system, that is atransdermal patch. Typically, a transdermal patch is a smallself-adherent bandage containing the active substance to be delivered.These bandages can have various forms and sizes. The simplest type is anadhesive monolith comprising an active substance stock on a carrier(cover layer). This active substance stock is typically formed in theform of an active substance layer of the active substance in apharmaceutically acceptable pressure-sensitive adhesive or contactadhesive and is in contact with the skin area, whereby the activesubstance is delivered into the body of the patient by transdermaldiffusion.

More complex patches are multiple laminates or patches with an activesubstance stock, wherein a further adhesive layer can be arrangedbetween the active substance layer and the skin.

One form of administration via transdermal patches of rivastigmine hasbeen already described in the basic patent on rivastigmine, GB 2203040.The transdermal patch disclosed therein consists of a cover layer and alayer forming the active substance layer. In addition to the activesubstance rivastigmine a hydrophilic polymer, a non-swelling acrylatepolymer, and a plasticizer are contained in the active substance layer.

After publication of the GB 2203040 further transdermal therapeuticsystems (TTS) i.a. containing rivastigmine as active substance have beendeveloped and described. In WO 02/03969 a TTS is described, wherein theactive substance-containing matrix layer additionally contains highlydisperse silica for increasing the skin permeation.

In the patent applications WO 2008/021113 and EP 2 016 939 there aredisclosed patches with a more complex structure that intended to ensurean administration of different active substances over a period of up toseven days. These patches, between the layer containing the activesubstance and an adhesive layer, additionally contain a membranecontrolling the delivery of the active substance. However, in the activesubstance layer of the patch free hydroxyl groups are present, because apolyhydric alcohol is contained in the active substance layer.

In DE 199 18 106 the active substance layer contains a self-adhesivepolymer having acrylic acid or methacrylic acid units with a definedcontent of carboxyl groups to increase the water-absorbing capacity aswell as tolerance of acidic polyacrylic contact adhesives to moisture.

WO 2007/064407 A1 discloses a TTS with a silicone-based adhesive layerto achieve an improvement in terms of the adhesive properties,tolerance, and safety in the rivastigmine therapy. According to WO2007/064407 A1 it is particularly preferred that the reservoir layercontains an antioxidant (page 7, 4^(th) paragraph). Accordingly, allformulations in the examples contain the antioxidant vitamin E. TheDurotak® 387-2353 used there is a polyacrylate having carboxyl groups.According to WO 2007/064407 A1, the reservoir layer is also supposed tocontain as penetration enhancer various substances such as, e.g.glycerin, fatty acids, etc. (page 7, 5^(th) paragraph). These substancesoften contain free hydroxyl or carboxyl groups that are thus present inthe polymer matrix of the reservoir layer. WO 2007/064407 A1 does notspecially deal with the stability of rivastigmine. In particular, WO2007/064407 A1 does not teach to select certain polymers for the polymermatrix of the reservoir layer to prevent the degradation ofrivastigmine.

US 2008/0044461 A1 discloses TTS formulations with donepezil (seeexamples). Rivastigmine is also mentioned (claim 7). US 2008/0044461 A1does not disclose any active substance layer with a polymer matrix.Rather, the release is controlled via a membrane (so-called membranepatches), not via a polymer skeleton into which the active substance isembedded (so-called matrix patches). Moreover, it is an essentialfeature of US 2008/0044461 A1 that the reservoir layer contains agel-forming agent and a permeation enhancer (see claim 1). Alcohols areused as the permeation enhancers (see, [0053]). Cellulose polymers areused as the gel-forming agents (see, [0055]). Thus, both the permeationenhancers and the gel-forming agents are compounds with free hydroxylgroups that are present in the TTS in the reservoir layer.

US 2007/0259028 A1 discloses TTS formulations with donepezil (see,examples). Rivastigmine is also mentioned (claim 3). It is an essentialfeature of US 2007/0259028 A1 that the reservoir layer contains apolyhydric alcohol, e.g. glycerin. That is, according to US 2007/0259028A1 free hydroxyl groups are inevitably present in the polymer matrix ofthe reservoir layer.

US 2004/0086552 A1 discloses TTS formulations with an active substancethat can be selected from a very long list (see [0070] to [0095]). Bothmatrix patches and “membrane patches” are disclosed (see [0057] and[0058], respectively). For the matrix patches, US 2004/0086552 A1 doesnot teach to select certain polymers for the matrix to stabilize theactive substance.

U.S. Pat. No. 6,689,379 B1 discloses TTS formulations with a particularadhesive layer. Also, rivastigmine is mentioned as a possible activesubstance. Preferably, the active substance layer is supposed to containa compound with hydroxyl groups, see claim 10. U.S. Pat. No. 6,689,379B1 does not teach to select certain polymers for the polymer matrix ofthe reservoir layer to prevent the degradation of rivastigmine.

However, the patent EP 1 047 409 reports a general problem with theadministration of rivastigmine by a TTS. It has been found thatespecially in the presence of oxygen the active substance is susceptibleto decomposition. In der transdermal composition disclosed in GB 2203040the rivastigmine decomposes according to the disclosure in EP 1 047 409also despite the formation of a closed polymer matrix around the activesubstance and an airtight package of the composition. In EP 1 047 409the problem of the low stability of rivastigmine is solved in that anantioxidant is added to the pharmaceutical composition.

Up to now, commercially acquirable TTS with rivastigmine permit only acontinuous administration over 24 hours. One object of the invention isto control the release over the extended time interval. With thetransdermal administration of rivastigmine over a prolonged period ithas to be ensured that (1) a sufficient chemical stability of the activesubstance rivastigmine is guaranteed, (2) a sufficient physicalstability (in particular in terms of cold flow) of the system isguaranteed, and (3) the system has a sufficient adhesiveness over theapplication period.

A further object of the present invention is to find therapeuticcompositions containing rivastigmine for the transdermal administrationthat are suitable for a therapeutic application period of several days.

SUMMARY OF THE INVENTION

It has been found that rivastigmine in transdermal patches issufficiently stable if the polymer matrix of the active substance layerdoes not contain any free hydroxyl groups or carboxyl groups. Thepresent invention is based, inter alia, on the selection of specialpolymers for the polymer matrix to thereby prevent or minimize,respectively, the degradation of rivastigmine.

Thus, the present invention provides a sufficiently stable TTScontaining rivastigmine and a method for the production of the same.

Thus, a first aspect of the present invention is a TTS for administeringrivastigmine for an application period of several days, which comprisesthe following components:

-   -   a) a cover layer,    -   b) an active substance layer on the cover layer which comprises        an active substance-containing polymer matrix,    -   c) a membrane on the active substance layer which controls the        release of rivastigmine;    -   d) an adhesive layer on the membrane which comprises a contact        adhesive; and    -   e) a pull-off layer on the adhesive layer,

wherein the polymer(s) of the active substance layer do(es) not containany free hydroxyl groups or carboxyl groups.

Moreover, the invention provides the use of polymers or copolymerswithout any free hydroxyl groups or carboxyl groups in a TTS containingrivastigmine and a TTS for the treatment of the Alzheimer's disease andParkinson's dementia.

Although in WO 2008/021113 the adhesive materials polyisobutylene,polyacrylate, and silicone-based adhesives are described as equallysuitable it has presently been found that polyisobutylenes are bettersuited as contact adhesive in the adhesive layer and that the propertiesof this adhesive are further improved by the addition of polybutene as atackifier. Thus, the present invention provides a TTS containing anactive substance and having improved adhesive properties, and a methodfor the production of the same.

Thus, a second aspect of the present invention is a transdermaltherapeutic system for administering an active substance through theskin comprising the layers arranged in the following order with respectto each other:

-   a) a cover layer,-   b) an active substance layer comprising a polymer matrix containing    the active substance,-   c) an adhesive layer comprising (1) a contact adhesive which    consists of a polyisobutylene or a mixture of several    polyisobutylenes, and (2) an adhesive enhancer which consists of    polybutene or a mixture of several polybutenes; and-   d) a pull-off layer.

A third aspect of the present invention is a TTS for administeringrivastigmine through the skin comprising a cover layer, an activesubstance layer containing the rivastigmine, the adhesive layer improvedaccording to the second aspect, and a pull-off layer for theadministration of rivastigmine over a period of at least two (e.g. twoor three) days wherein a membrane controlling the release ofrivastigmine is present between the active substance layer and theadhesive layer. Thus, a third aspect of the present invention is atransdermal therapeutic system for administering an active substancethrough the skin comprising the layers arranged in the following orderwith respect to each other:

-   a) a cover layer,-   b) an active substance layer comprising an active    substance-containing polymer matrix,-   c) a membrane controlling the release of the rivastigmine;-   d) an adhesive layer comprising (1) a contact adhesive which    consists of a polyisobutylene or a mixture of several    polyisobutylenes, and (2) an adhesive enhancer which consists of    polybutene or a mixture of several polybutenes; and-   e) a pull-off layer.

A fourth aspect of the present invention is a TTS for administeringrivastigmine through the skin comprising a cover layer, an activesubstance layer containing rivastigmine, the adhesive layer improvedaccording to the second aspect, and a pull-off layer, wherein the activesubstance layer has no free hydroxyl groups or carboxyl groups. Thus,the fourth aspect of the present invention is a transdermal therapeuticsystem for administering an active substance through the skin comprisingthe layers arranged in the following order with respect to each other:

-   a) a cover layer,-   b) an active substance layer comprising a polymer matrix containing    the active substance,-   c) an adhesive layer comprising (1) a contact adhesive which    consists of a polyisobutylene or a mixture of several    polyisobutylenes, and (2) an adhesive enhancer which consists of    polybutene or a mixture of several polybutenes, and-   d) a pull-off layer,

wherein the polymer(s) of the active substance layer does not containany free hydroxyl groups or carboxyl groups.

A fifth aspect of the present invention is the provision of a TTS foradministering rivastigmine through the skin comprising a cover layer, anactive substance layer containing the rivastigmine, the adhesive layerimproved according to the invention, and a pull-off layer, wherein atleast the active substance layer, but preferably the entire TTS, has noantioxidants. Thus, the fifth aspect of the present Invention is atransdermal therapeutic system for administering an active substancethrough the skin comprising the layers arranged in the following orderwith respect to each other:

-   a) a cover layer,-   b) an active substance layer comprising a polymer matrix containing    the active substance,-   c) an adhesive layer comprising (1) a contact adhesive which    consists of a polyisobutylene or a mixture of several    polyisobutylenes, and (2) an adhesive enhancer which consists of    polybutene or a mixture of several polybutenes, and-   d) a pull-off layer,

wherein at least the active substance layer, but preferably the entireTTS, has no antioxidants.

The above-mentioned various aspects of the invention can be arbitrarilycombined with each other. The active substance within the meaning of thepresent invention is rivastigmine or a physiologically compatible salt,hydrate, solvate, or derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

An “antioxidant” within the meaning of the present invention is apharmaceutically acceptable compound or composition that decelerates,inhibits, disrupts, and/or retards the oxidation processes. Inparticular, antioxidants include the following substances: tocopherolsand their esters, the Sesamol of sesame oil, the coniferyl benzoate ofbenzoin, nordihydroguaiac resin and -guaiaretic acid (NDGA), gallates(methyl, ethyl, propyl, amyl, butyl, lauryl a.o. gallates), butylatedhydroxyanisole (BHT, also called butyl-p-cresol); ascorbic acid andsalts and esters thereof (e.g. ascorbyl palmitate), erythorbic acid(iso-ascorbic acid) and salts and esters thereof, monothioglycerol,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite,sodium sulfite, potassium metabisulfite, butylated hydroxyanisole,butylated hydroxytoluene, propionic acid.

The term “tocopherol” also includes tocopherol esters. A knowntocopherol is α-tocopherol. The term “α-tocopherol” includes esters ofα-tocopherol (e.g. α-tocopherol acetate).

A “polymer matrix” is a solid or semi-solid composition having a threedimensional structure which comprises a polymer or a mixture ofpolymers. The polymer matrix is also referred to as polymer skeletonsince the three dimensional skeleton structure is as a rule provided bythe polymer or mixture of polymers. Other substances, e.g. an activesubstance, may be embedded in the polymer matrix. Preferably, the activesubstance is evenly distributed in the polymer matrix.

In the following, the features of the TTS according to the invention aredescribed in more detail and, unless it is explicitly stated otherwise,the respective explanations on the individual features refer to all ofthe preceding aspects of the present invention.

Moreover, the preceding aspects of the present invention can bearbitrarily combined to further preferred embodiments. So, for examplein a preferred TTS the active substance layer is free of tocopherols,and the polymer(s) of the polymer matrix of said active substance layercontain(s) neither hydroxyl groups nor carboxyl groups. Additionally, inthis embodiment a membrane controlling the release of rivastigmine ispreferably present between the active substance layer and the adhesivelayer, and the TTS is suited for an application period of at least two,at least three or at least four days, e.g. for two to seven, for threeto six, or for four to five days.

In the TTS according to the invention the active substance rivastigmineis sufficiently stable. “Sufficiently stable” means that the impuritiesof the active substance after one month of storage at 40° C. and 75%relative air humidity in total are not more than 1% by weight,preferably not more than 0.5% by weight, based on the desired content ofactive substance in the formulation. Impurities of the active substancein the formulation are degradation products of the active substancerivastigmine and impurities introduced with the active substance intothe formulation (e.g. traces of intermediate products from theproduction of the active substance).

The stability and amount, respectively, of impurities can be determinedas described in example 4. Preferably, the total content of thedecomposition products/impurities after three months of storage at 40°C. and 75% relative air humidity is less than 1% by weight, preferablyless than 0.6% by weight. It is also preferred that the total content ofthe decomposition products/impurities after six months of storage at 40°C. and 75% relative air humidity is less than 1% by weight. It is alsopreferred that the total content of impurities after one month ofstorage at 25° C. and 60% relative air humidity is less than 0.25% byweight. It is further preferred that the total content of impuritiesafter three and after six months of storage at 25° C. and 60% relativeair humidity is less than 0.5% by weight. The information on “% byweight” of impurities always refer to the desired content of activesubstance in the formulation, unless stated otherwise.

The application period of a TTS according to the invention is preferablyat least two or at least three days. In a special embodiment the TTSaccording to the invention is suitable for an application period of 2 to4, 2 to 5, 2 to 6, 2 to 7, or 3 to 8 days.

Preferably, the active substance layer, more preferably the entire TTS,has no tocopherol. In a further embodiment the active substance layer,preferably the entire TTS, has no tocopherol and no butylatedhydroxyanisole (BHT, also called butyl-p-cresol). In a furtherembodiment the active substance layer, preferably the entire TTS, has notocopherol, no butylated hydroxyanisole, and no butylatedhydroxytoluene. In a particular embodiment the active substance layer,preferably the entire TTS, has none of the following antioxidants:tocopherols and their esters, the Sesamol of sesame oil, the coniferylbenzoate of benzoin, nordihydroguaiac resin and -guaiaretic acid (NDGA),gallates (methyl, ethyl, propyl, amyl, butyl, lauryl a.o. gallates),butylated hydroxyanisole (BHT, also called butyl-p-cresol); ascorbicacid and salts thereof, ascorbyl palmitate, erythorbic acid(iso-ascorbic acid) and salts thereof, monothioglycerol, sodiumformaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodiumsulfite, potassium metabisulfite, butylated hydroxyanisole, butylatedhydroxytoluene, propionic acid. In a special embodiment the activesubstance layer, more preferably the entire TTS, has no antioxidants atall.

However, it is quite possible that in the TTS of the present inventionantioxidants can be present as long as these do not negatively affectthe TTS's mode of action. Here, it has to be noted that for stabilizingrivastigmine according to one aspect of the present invention noantioxidants are necessary. However, antioxidants can also be employedfor other purposes in the TTS according to the invention. Thus, it ispossible, although not preferred, that the TTS according to theinvention does contain antioxidants, e.g. tocopherols such asα-tocopherol and its esters, butylated hydroxytoluene and butylatedhydroxyanisole.

The total amount of antioxidant in the TTS of the present invention istypically less than 1% by weight or less than 0.1% by weight, morepreferably less than 0.05% by weight, most preferably less than 0.01% byweight, each based on the weight of the total formulation (without coverand pull-off layer).

Structure of the TTS

The structure of the TTS according to the invention comprises severallayers. The cover layer is on the end of the TTS that is in use turnedaway from the skin. The active substance layer is at the side of thecover layer that faces the human skin in use. Moreover, the adhesivelayer is at the side of the active substance layer that faces the humanskin in use. Before the TTS is used, the pull-off layer is at the sideof the adhesive layer that faces the human skin in use, which is removedright before the use of the TTS. Preferably, a membrane controlling therelease of the active substance is present between the active substancelayer and the adhesive layer.

The area of the TTS according to the invention is not particularlylimited. Typically, the area is about 5-40 cm², but can thoroughly begreater or smaller.

In one embodiment, the area of the cover layer of the TTS according tothe invention corresponds at least to the area of the active substancelayer or the adhesive layer, respectively. However, it can also begreater than that of the active substance layer so that it not onlycompletely covers the active substance layer but also extends beyond theedge of the active substance layer. However, in such an embodimenteither the area of the adhesive layer should be equal to the area of thecover layer, or the side of the cover layer that faces the skin shouldhave a further adhesive layer in order to ensure that the entire surfaceof the TTS that faces the skin in use adheres to the skin. In anotherembodiment the cover layer is somewhat smaller than the area of theactive substance layer and/or adhesive layer.

Active Substance Layer

The active substance layer of the TTS according to the inventioncontains the active substance, preferably rivastigmine, embedded in apolymer matrix. According to the first aspect of the invention thepolymer matrix comprises substantially no polymers or copolymerscontaining free hydroxyl groups or free carboxyl groups. Preferably, thepolymer matrix contains substantially no free hydroxyl groups and nofree carboxyl groups. Preferably, the polymer matrix containssubstantially no free amino groups, no free hydroxyl groups, and no freecarboxyl groups. Preferably, the polymer matrix is formed of polymersand/or copolymers containing substantially no free hydroxyl groups andno free carboxyl groups. Still more preferably, the polymer matrix isformed of polymers and/or copolymers containing no amino groups, no freehydroxyl groups, and no free carboxyl groups.

Suitable polymers or copolymers without free functional groups that formthe polymer matrix are particular polyacrylates, acrylate-vinylacetatecopolymers, polyisobutylene and styrene-butadiene copolymers which an bepresent individually or as blend.

As suitable polyacrylates containing substantially no free functionalgroups polymers (homopolymers, copolymers, and block-copolymers) on thebasis of acrylic acid esters and/or methacrylic acid esters can be used.As monomers for the production of suitable polyacrylates here, inparticular n-butyl acrylate, n-butyl methacrylate, ethyl acrylate,2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methylmethacrylate, tert-butyl acrylate, sec-butyl acrylate, tert-butylmethacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate,isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate,isopropyl methacrylate and mixtures of these monomers are possible.These monomers are esters of the acrylic or methacrylic acid,respectively, that carry linear, branched or cyclic aliphatic C₁-C₁₂substituents without other free functional groups. Also vinyl acetatecan be used as a co-monomer together with at least one of these monomersfor the production of the polyacrylate.

Preferably, the polymer matrix consists of one or more polyacrylatescontaining substantially no free functional groups. More preferably, thepolymer matrix consists of polyacrylates prepared by the polymerizationof acrylic acid esters and/or methacrylic acid esters. In a particularembodiment, the polymer matrix consists of polyacrylates prepared by thepolymerization of acrylic acid esters and/or methacrylic acid esters,with the acrylic acid esters and/or methacrylic acid esters beingselected from the group consisting of n-butyl acrylate, n-butylmethacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate,methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec-butylacrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexylmethacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropylacrylate, isopropyl methacrylate, and mixtures thereof. In anotherembodiment the polymer matrix substantially consists of polyacrylatesprepared by the copolymerization of acrylic acid esters and/ormethacrylic acid esters with vinyl acetate, wherein the acrylic acidesters and/or methacrylic acid esters are selected from the groupconsisting of n-butyl acrylate, n-butyl methacrylate, ethyl acrylate,2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methylmethacrylate, tert-butyl acrylate, sec-butyl acrylate, tert-butylmethacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate,isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate,isopropyl methacrylate, and mixtures thereof.

Particularly preferred are copolymers prepared from the startingmonomers 2-ethylhexyl acrylate and vinyl acetate, e.g. an acrylate-vinylacetate copolymer which is prepared to 50% each of the starting monomers2-ethylhexyl acrylate and vinyl acetate (Duro-Tak® 87-4098). Alsopreferred is the acrylate polymer Duro-Tak® 87-9088 (also an acrylatepolymer without free functional groups) available from Henkel. In aspecial embodiment the acrylate polymer Duro-Tak® 87-900A or Duro-Tak®87-9301 is used for the polymer matrix.

The total proportion of monomers containing free hydroxyl groups or freecarboxyl groups (e.g. acrylic acid, methacrylic acid, and esters of theacrylic acid or methacrylic acid, respectively, that carry functionalgroups, in particular the hydroxyl groups-containing esters) is below 1%by weight, preferably below 0.5% by weight, more preferably below 0.2%by weight; based on the mixture of monomers the polymer matrix isprepared of. In a particular embodiment the total proportion of saidmonomers is below 0.1% by weight. In a particular embodiment no freehydroxyl groups and no free carboxyl groups are contained in the mixtureof monomers.

Certainly, a TTS containing polyacrylates substantially free of hydroxylgroups and carboxyl groups as the active substance-containing polymermatrix has been already described in WO 03/017988 A1, but not inconnection with the active substance rivastigmine. The object describedin WO 03/017988 was to solve the drawback of the low active substanceutilization of a TTS. According to this disclosure said object has beensolved by polymer matrices which ideally are free of hydroxyl groups orcarboxyl groups. In this printed matter, the active substancerivastigmine is not mentioned, let alone an effect enhancing thestability of rivastigmine.

According to one aspect of the invention the active substance layercontains substantially no polymers or copolymers containing freehydroxyl groups or free carboxyl groups. Preferably, the activesubstance layer contains substantially no free hydroxyl groups and nofree carboxyl groups. More preferably, the active substance containssubstantially no free amino groups, no free hydroxyl groups, and no freecarboxyl groups. In a particular embodiment, also the adhesive layercontains substantially no polymers or copolymers containing freehydroxyl groups or free carboxyl groups. Preferably, the adhesive layercontains substantially no free hydroxyl groups and no free carboxylgroups. More preferably, the adhesive layer contains substantially nofree amino groups, no free hydroxyl groups, and no free carboxyl groups.

Preferably, the active substance layer contains 30-50% by weight ofrivastigmine and 50-70% by weight of the polymer matrix, based on thetotal weight of the active substance layer. In a particularly preferredembodiment of the TTS according to the invention the active substancelayer contains about 40% by weight of rivastigmine and about 60% byweight of the polymer matrix. Preferably, the active substance layer inaddition to the active substance and the polymer matrix contains nofurther constituents. However, it is possible that additionally furtheradditives known in the prior art are contained in the active substancelayer. Thus, for example plasticizers or gel-forming agents mayadditionally be present in the active substance layer.

The absolute amount of rivastigmine depends on different factors, inparticular the size of the TTS to be used, the base weight, and theactive substance concentration in the active substance layer. The baseweights of the dried active substance layer matrix preferably are in therange of 20-100 g/m², more preferred in the range of 25-80 g/m², andstill more preferred in the range of 30-70 g/m². The active substancelayer can have a thickness (dry thickness) in the range of 20-400 μm or30-200 μm or 40-100 μm. Also other thicknesses than those mentionedabove are possible.

Intermediate Membrane

Preferably, the membrane that according to one aspect of the presentinvention lies between the active substance layer and the adhesive layerand controls the release of the active substances (also referred to as“control membrane”) consists of a polyolefine such as for examplepolypropylene (e.g., Celgard® 2400) or particularly preferred ofpolyethylene (e.g., CoTran™ 9719 or CoTran™ 9720) or more preferably ofpolyethylene with a vinyl acetate proportion of 4.5 to 19% (e.g.,CoTran™ 9707, CoTran™ 9702, CoTran™ 9728). Moreover, the membranes canhave a porosity of up to 90% (e.g. Solupor® 10P05A, Celgard® 2400).

Porous membranes or coherent membranes may be used.

The porosity of the porous membranes can be up to about 90%. Data ofpreferred porous membranes are:

Solupor® 10P05A (polyethylene, porosity: 83%, thickness: 60 μm)

Celgard® 2400 (polypropylene, porosity: 41%, thickness: 25 μm)

Data of preferred coherent membranes are:

CoTran™ 9719 (polyethylene, thickness: 43.2 μm)

CoTran™ 9720 (polyethylene, thickness: 76.2 μm)

CoTran™ 9707 (polyethylene with 4.5% vinyl acetate, thickness: 50.8 μm)

CoTran™ 9702 (polyethylene with 9.0% vinyl acetate, thickness: 50.8 μm)

CoTran™ 9728 (polyethylene with 19.0% vinyl acetate, thickness: 50.8 μm)

Typically, the membrane has a thickness of 0.01 and 0.15 mm. Thepreferred thickness of the membrane is 0.025 to 0.080 mm.

According to the invention it is preferred to use a coherent membranesubstantially consisting of polyethylene with a thickness of about 40 to80 μm (e.g., CoTran™ 9720). According to the invention it is alsopreferred to use a coherent membrane substantially consisting ofpolyethylene with about 19.0% vinyl acetate (e.g., CoTran™ 9728).According to the invention it is most preferred to use a coherentmembrane substantially consisting of polyethylene with a thickness ofabout 40 to 50 μm (e.g. CoTran™ 9719).

The membrane is the essential formulation constituent in order to ensurea controlled delivery of the active substance over several days. Thedrug delivery can be controlled by the vinyl acetate proportion in themembrane, inter alia.

Adhesive Layer

Preferably, the adhesive layer of the TTS according to the inventioncontains polyisobutylene as contact adhesive and optionally polybuteneto improve the adhesiveness. Polyisobutylene is a self-adherent contactadhesive that does not cure and thus, maintains its adhesive propertiesover a long period. Preferably, polyisobutylenes with different averagemolecular weights as a mixture are used. Polyisobutylene is available invarious average molecular weights. The term “average molecular weight”in connection with polyisobutylene in the present application refers tothe so-called viscosity average M_(V). The viscosity average M_(V) isdetermined from the solution viscosity of a solution of thepolyisobutylene in isooctane at 20° C. As the measuring device there isused an Ubbelohde viscometer. The viscosity average M_(V) is calculatedfrom the following equation:

$M_{V} = \sqrt[0.65]{\frac{J_{o} \times 10^{2}}{3.06}}$

The estimation of the intrinsic viscosity J₀ required for thedetermination of the viscosity average M_(V) is done according to theSchulz-Blaschke relationship from the specific viscosity η_(SP) measuredand the solution concentration.

J ₀=η_(sp) /c(1+0.31×η_(sp)) cm³/g  (Schulze-Blaschke relationship)

The specific viscosity η_(SP)=t/t₀−1, wherein t and to are the flow timeof the solution or the solvent (each with Hagenbach-Couette correction),respectively, and c is the concentration of the solution in g/cm³.Optionally, the regulation DIN 53728 may be additionally considered.

Suitable average molecular weights M_(V) of polyisobutylene are forexample in the range of about 40,000 g/mol to about 4,000,000 g/mol. Apossible mixture is that of (1) polyisobutylene with an averagemolecular weight M_(V) of about 40,000 g/mol (e.g., Oppanol® B10,available from BASF) and (2) polyisobutylene having an average molecularweight M_(V) of more than about 1,000,000 g/mol (z. B. Oppanol® B100,available from BASF, with an average molecular weight M_(V) of about1,110,000 g/mol). It is within the knowledge of the skilled person tomix the various molecular weights in the suitable ratio such as toachieve the desired properties of the adhesive layer.

The polyisobutylene in the adhesive layer may have a molecular weightdistribution having a first relative maximum between 30,000 g/mol and100,000 g/mol, and a second relative maximum between 300,000 g/mol and500,000 g/mol. More preferably, the first relative maximum is between35,000 g/mol and 50,000 g/mol and independently, the second relativemaximum is between 350,000 g/mol and 450,000 g/mol. Most preferably, thefirst relative maximum is about 40,000 g/mol, and independently, thesecond relative maximum is about 400,000 g/mol.

The polyisobutylene mixture of the contact adhesive can be obtained bymixing a first polyisobutylene polymer with an average molecular weightM_(V) between 30,000 g/mol and 100,000 g/mol with a secondpolyisobutylene polymer with an average molecular weight M_(V) between300,000 g/mol and 500,000 g/mol. Preferably, the first polyisobutylenepolymer has an average molecular weight M_(V) between 35,000 g/mol and50,000 g/mol, most preferably of about 40,000 g/mol. Preferably, thesecond polyisobutylene polymer has an average molecular weight M_(V)between 350,000 g/mol and 450,000 g/mol, most preferably of about400,000 g/mol.

The most preferred mixture is that of (1) polyisobutylene with anaverage molecular weight M_(V) of about 40,000 g/mol (for exampleOppanol® B10 SFN, available from BASF) and (2) polyisobutylene with anaverage molecular weight M_(V) of about 400,000 g/mol (for exampleOppanol® B50 SF, available from BASF).

The proportion of the two polyisobutylene polymers in the mixture canvary. The weight ratio of the first polyisobutylene polymer to thesecond polyisobutylene polymer in the mixture can be 10:1 to 1:10,preferably 2:1 to 1:2, most preferably 3:2 to 2:3. In particularlypreferred embodiments, the polyisobutylene polymer of the contactadhesive consists of 40 to 60% by weight Oppanol® B10 (for exampleOppanol® B10 SFN) and 60 to 40% by weight Oppanol® B50SF.

Preferably, the adhesive layer improved according to the inventionadditionally contains polybutene. Suitable average molecular weightsM_(N) of polybutene are for example in the range of about 500 to 10,000g/mol. Also polybutene preferably is present in a mixture of differentaverage molecular weights. A preferred mixture is that of (1) polybutenewith an average molecular weight M_(N) of about 900 g/mol (e.g.,Indopol® H-100, with an average molecular weight M_(N)=910 g/mol,available from Ineos) and (2) polybutene with an average molecularweight M_(N) of about 6,000 g/mol (e.g., Indopol® H-18000, availablefrom Ineos).

Another preferred mixture is that of (1) polybutene with an averagemolecular weight M_(N) of about 900 g/mol (e.g. Indopol® H-100, with anaverage molecular weight M_(N)=910 g/mol, available from Ineos) and (2)polybutene with an average molecular weight M_(N) of about 2,500 g/mol(e.g. Indopol® H-1900, available from Ineos).

Particularly preferred is the mixture of (1) polybutene with an averagemolecular weight M_(N) of about 2,500 (e.g. Indopol® H-1900, availablefrom Ineos) and (2) polybutene with an average molecular weight M_(N) ofabout 6,000 g/mol (e.g. Indopol® H-18000). It is within the knowledge ofthe skilled person to mix the various molecular weights in a suitableratio such that the desired properties of the adhesive layer in terms ofadhesiveness and release rate of the active substance are achieved inthe system.

The proportions of two polybutenes in the adhesive layer can vary. Theweight ratio of the first polybutene to the second polybutene ispreferably 2:1 to 1:2, most preferably 3:2 to 2:3. In a particularlypreferred embodiment the polybutene polymer in the adhesive layerconsists of 40% by weight of polybutene with an average molecular weightM_(N) of about 2,500 g/mol and about 60% by weight of polybutene with anaverage molecular weight M_(N) of 6,000 g/mol.

The “average molecular weight M_(N)” is the number-average molar massand can be determined according to “American Standard” ASTM D3536-91 orASTM D5296-05.

The constituents of the improved adhesive layer according to theinvention, polyisobutylene and polybutene, are preferably present in aweight ratio of 4:1 to 1:2, more preferably 3:1 to 1:2. For example,polyisobutylene and polybutene can be present in a weight ration ofabout 1:1. In another embodiment, polyisobutylene and polybutene arepresent in a weight ratio of about 7:3.

Preferably, the adhesive layer contains about 10 to about 90% by weight,preferably about 25 to about 75% by weight, most preferably about 40 toabout 70% by weight of polyisobutylene (e.g., about 50% by weight orabout 70% by weight), based on the total weight of the adhesive layer.These proportions indicate the total content of polyisobutylene orpolyisobutylene mixture in the adhesive layer. Preferably, the adhesivelayer also contains about 5 to about 80% by weight, preferably about 15to about 60% by weight, most preferably about 25 to about 50% by weightpolybutene (e.g. about 50% by weight or about 30% by weight), based onthe total weight of the adhesive layer. These proportions indicate thetotal content of polybutene or polybutene mixture, respectively, in theadhesive layer.

In a preferred embodiment, the adhesive layer does not contain anyacrylate polymer and acrylate copolymer.

The thickness of the adhesive layer (dry thickness) is not particularlylimited. It can be in a range of about 10-300 μm, or in a range of70-140 μm. The absolute amount of the adhesive layer can be about 10-50g/m², or 20-40 g/m², without being limited thereto.

Generally, the adhesive layer contains 60-100% by weight of the contactadhesive (e.g. polyisobutylene) or the mixture of contact adhesives,respectively, including adhesive enhancer (e.g. polybutene). Furtherpossible constituents of the adhesive layer are plasticizers andgel-forming agents.

Suitable plasticizers are known in the prior art, with these preferablybeing mineral oil, neutral oil, paraffin, linseed oil, octyl palmitate,squalene, squalane, silicone oil, isobutyl myristate, isostearylalcohol, and/or oleyl alcohol, more preferably mineral oil, neutral oil,and/or paraffin. Mineral oils are colorless clear hydrocarbons. They arerecovered from the distillation fractions of petroleum that boil aboveabout 300° C. and are liberated from solid hydrocarbons by cooling. Bysuitable fractionation, mineral oils can be recovered that are liquid atbody temperature, that is at about 35-37° C., and are solid at lowtemperatures, in particular at temperatures below 20° C. The choice ofthe mineral oil with a liquefaction point of about 30-35° C. ispreferred. Particularly preferred are the paraffins and mineral oilsthat correspond to the requirements of the Ph. Eur. 6 and/or USP 32-NF27.

In general, the plasticizer is present in the adhesive layer in anamount in the range of 0-40% by weight, or 1-10% by weight, or in therange of 2-5% by weight, for example 2% by weight, based on the totalweight of the adhesive layer.

Preferably, the gel-forming agent is a gel-forming agent with aparticulate structure and a high concentration of polar groups on itssurface. These cause correspondingly high interfacial tensions towardsthe oils that are partially compensated by agglomeration of theparticles among themselves into gel skeletons. Accordingly, the gelskeletons are always the more solid the bigger the difference inpolarity is between the oils and the surface of the skeleton formingagent. According to the invention it is preferred to use highly dispersesilica or pyrogenic silicic acid as the gel-forming agent. The size ofthe particles preferably is in the nanometer range and is for example inthe range of 400-1500 nm, in particular in the range of 500-1000 nm.Pyrogenic silicic acid is for example sold under the designationCAB-O-SIL® and is a known thickener for mineral oils. Another example ofsuitable gel-forming agents is bentonite. Also, the sodium carbomerknown as a gel-forming agent can be used.

The gel-forming agent is preferably used in an amount of 0-4.0% byweight, more preferably 0.1-2.0% by weight, still more preferably0.5-2.0% by weight, based on the weight of the adhesive layer.

In a particularly preferred embodiment of the TTS according to theinvention the adhesive layer consists of 99.5% by weight of mixtures ofpolyisobutylene with different molecular weights and polybutene withdifferent molecular weights and of 0.5% by weight of a gel-formingagent, preferably highly disperse silica or pyrogenic silicic acid,based on the total weight of the adhesive layer.

Cover Layer

Preferably, the cover layer of the TTS according to the invention isocclusive, that is ending. In a preferred embodiment such cover layerscan consist of polyolefins, in particular polyethylene, or polyesters aswell as polyurethanes. Also layers containing several different polymersarranged on top of each other can preferably be used. Suitable materialscomprise polyolefin, cellophan, cellulose acetate, ethyl cellulose,vinyl acetate-vinyl chloride copolymers provided with plasticizers,ethylene-vinylacetate copolymers, polyethylene terephthalate, nylon,polyethylene, polypropylene, polyvinylidene chloride,ethylene-methacrylate copolymers, paper which can optionally be coated,textile tissue, aluminum foil, and polymer-metal composite materials.Polyester foils, such as polyethylene terephthalate foils areparticularly preferred. As is common in the prior art, the thickness ofthe back layer may be for example 10 μm to 100 μm, for example about 40μm (nominal thickness). Especially preferred are composite foils ofpigmented PE, PETP, and aluminum.

Pull-Off Layer

According to the invention, on the adhesive layer there is a pull-offlayer, also referred to as “release liner”. Preferably, said pull-offlayer is prepared from polymeric material that optionally can also bemetallized. Examples of preferably used materials are polyurethanes,polyvinylacetate, polyvinylidene chloride, polypropylene, polycarbonate,polystyrene, polyethylene, polyethylene terephthalate, polybutyleneterephthalate as well as paper that is optionally surface coated withcorresponding polymers. Preferably it is a pull-off layer that isfluoropolymer-coated or siliconized on one or both sides. Particularlypreferred are usual fluoropolymer-coated or siliconized polyester foils,such as the one-sided siliconized commercial products Primeliner 100 μmand Perlasic LF 75 μm (Loparex, NL and Perlen Converting AG,Switzerland) or the one-sided fluoropolymer-coated products such as e.g.ScotchPak 1022 (3M Drug delivery).

Further Aspects and Embodiments

A particularly preferred embodiment of the TTS according to theinvention is a TTS for administering an active substance through theskin comprising:

-   -   a) a cover layer,    -   b) an active substance layer on the cover layer that contains        30-50% by weight of the active substance and 50-70% by weight of        the polymer matrix, based on the total weight of the active        substance layer, wherein the polymer matrix substantially        consists of an acrylate polymer without hydroxyl groups and        without carboxyl groups, or substantially consists of an        acrylate copolymer without hydroxyl groups and without carboxyl        groups, and wherein the active substance is rivastigmine or a        physiologically compatible salt, hydrate, solvate, or derivative        thereof;    -   c) a membrane on the active substance layer that controls the        release of the rivastigmine;    -   d) an adhesive layer on the membrane that consists of 0-1% by        weight silica and 99-100% by weight of a mixture of a        polyisobutylene polymer with an average molecular weight M_(V)        of about 40,000 g/mol, a polyisobutylene polymer with an average        molecular weight M_(V) of about 400,000 g/mol, a polybutene        polymer with an average molecular weight M_(N) of about 2,500        g/mol and a polybutene polymer with an average molecular weight        M_(N) of about 6,000 g/mol; and    -   e) a pull-off layer on the adhesive layer.

Particularly, the amount of antioxidant in the entire formulation ofthis embodiment without cover and pull-off layer is less than 0.1% byweight, preferably less than 0.01%.

In a particularly preferred embodiment the TTS according to theinvention has no antioxidant selected from the group consisting ofvitamin E and esters thereof, butylated hydroxytoluene and butylatedhydroxyanisole.

Preferably, the TTS according to the invention has a substantiallylinear permeation profile. Here, the permeation is substantially linearover a period of at least 24 hours, preferably at least 48 hours, morepreferably at least 72 hours, most preferably at least 96 hours, or atleast 120 hours, or at least 144 hours, or at least 168 hours. Thepermeation can be determined by permeation tests per se known to theskilled person, for example by the in vitro permeation test according to“OECD GUIDELINE FOR THE TESTING OF CHEMICALS. Skin Absorption: in vitromethod.” Test Guideline 428. Adopted 13 Apr. 2004: 1-8. Preferably, theterm “substantially linear” means that the permeation rate, expressed inamount permeated per unit of time and unit area, is not significantlychanged over a prolonged time interval so that the permeation profilehas a substantially linear course. However, in particular in the initialphase a so-called period of latency can occur, wherein the permeationnot yet has the constant permeation rate, and moreover, the permeationrate may be reduced at very late time points due to a very strongdischarge of the system.

In a particular embodiment the average release rate in vivo is between0.1 mg/d/cm² and 2 mg/d/cm², preferably between 0.2 mg/d/cm² and 1mg/d/cm² and most preferably at least 0.3 mg/d/cm².

A further aspect of the present invention is to provide a method for theproduction of the TTS according to the invention. The method comprises

-   i) the preparation of a component containing the active substance    layer that contains the cover layer and the active substance layer,    which is on the side of the cover layer that is supposed to be the    side facing the skin;-   ii) the preparation of a component containing the adhesive layer    that contains the pull-off layer and the adhesive layer on the    pull-off layer and optionally a membrane controlling the release of    the active substance;-   iii) laminating onto each other the components of i) and ii) such    that the cover and pull-off layer in the cross-section of the    finished TTS represent the opposing outermost layers.

One embodiment of the method comprises:

-   -   i) applying and optionally subsequent drying of a film of a        composition forming the active substance layer, optionally in        the form of a solution or dispersion in a suitable medium, onto        the side of the cover layer supposed to be the side facing the        skin, and optionally backing with the membrane controlling the        release of the active substance;    -   ii) applying and optionally subsequent drying of a film of a        composition forming the adhesive layer, optionally in the form        of a solution or dispersion in a suitable medium, onto the        pull-off layer; and    -   iii) laminating onto each other the components of i) and ii)        such that the cover and pull-off layer in the cross-section of        the finished TTS represent the opposing outermost layers.

Another embodiment of the method comprises:

-   -   i) applying and optionally subsequent drying of a film of a        composition forming the active substance layer, optionally in        the form of a solution or dispersion in a suitable medium, onto        a siliconized pull-off foil (“intermediate liner”) and backing        with the cover layer;    -   ii) pulling off the siliconized pull-off foil (“intermediate        liner”) and backing with the membrane controlling the release of        the active substance;    -   iii) applying and optionally subsequent drying a film of a        composition forming the adhesive layer, optionally in the form        of a solution or dispersion in a suitable medium, onto the        pull-off layer; and    -   iv) laminating onto each other the components of ii) and iii)        such that the cover and pull-off layer in the cross-section of        the finished TTS represent the opposing outermost layers.

The preparation of a preferred TTS may be performed by firstlydispersing or dissolving, respectively (unless the polymer is alreadydissolved) the components for the active substance layer, that is theactive substance (preferably rivastigmine) and the matrix-formingpolymer or copolymer, respectively, or a mixture thereof, in an organicsolvent such as heptane or ethyl acetate. Typically, the matrix-formingpolymer or copolymer or the mixture thereof is already present in asolvent. Here, according to the invention a polymer and/or copolymer isused that is as defined above in connection with the TTS according tothe invention, that is a polymer and/or copolymer without hydroxylgroups and without carboxyl groups. The embodiments of the polymermatrix mentioned above as being preferred correspondingly apply to themethod according to the invention. In the preparation of the activesubstance layer there is preferably used a volatile organic solvent.Then, said mixture is applied to the cover layer as a uniform layer anddried. In case that a membrane controlling the release of the activesubstance is to be applied, after the active substance layer is driedthis can be applied to the side of the active substance layer oppositeto the cover layer, instead of the “intermediate liner”. Preferably, thecomponent for the active substance layer for protection is provided witha foil, preferably a siliconized polyester foil, also referred to as“intermediate liner”, that is applied to the side of the activesubstance layer opposite to the cover layer. Alternatively orequivalent, at first the mixture can also be applied to the“intermediate liner” and dried, with the cover layer being subsequentlyapplied to the side of the active substance layer opposite to the“intermediate liner”. The “intermediate liner” is removed right beforethe active substance layer component is fit together with the componentcontaining the adhesive layer. Optionally, after pulling off the“intermediate liner” also the control membrane can be backed before thefitting with the adhesive layer is performed.

In a separate step, the adhesive layer is prepared by dispersing thepolymer mixture forming the contact adhesive (and dissolved in anorganic solvent), preferably polyisobutylene of different averagemolecular weights, optionally together with adhesive enhancer,gel-forming agent and/or the plasticizer in an organic solvent such asheptane. However, it is preferred that the contact adhesive and theadhesive enhancer and/or plasticizer are dissolved in the organicsolvent and subsequently the gel-forming agent is dispersed in thissolution. Then, said mixture is applied to the pull-off film and allowedto dry. The embodiments of the adhesive layer mentioned above as beingpreferred correspondingly apply to the method according to theinvention.

The components obtained in these two process steps are subsequentlylaminated together, namely preferably such that the adhesive layer isdirectly applied to the active substance layer. In the embodiments wherea membrane is used the adhesive layer is applied to the membrane.Subsequently, pieces of the desired size can be punched from thefinished laminated foil and packaged.

In the individual process steps the organic solvents required todissolve or disperse the respective components are removed by subjectingthe products to increasing temperatures, optionally also using a partialvacuum.

A further aspect of the present invention is the use of a polymer orcopolymer having neither amino groups nor hydroxyl groups nor carboxylgroups in a TTS containing rivastigmine that is suitable for anapplication period of at least two or at least three days (e.g. two,three, four, five, six, or seven days). The use of polyacrylates,acrylate-vinyl acetate copolymers, polyisobutylene, andstyrene-butadiene copolymers as defined above is preferred. According tothe invention, these polymers or copolymers represent the polymer matrixof the active substance layer in which the active substance rivastigmineis embedded.

A further aspect of the invention is the use of a polymer or copolymerhaving no free hydroxyl groups and no free carboxyl groups to stabilizerivastigmine in a TTS, or to reduce the degradation of rivastigmine in aTTS. A further aspect of the invention is the use of a polymer orcopolymer having neither free amino groups nor free hydroxyl groups norfree carboxyl groups to stabilize rivastigmine in a TTS, or to reducethe degradation of rivastigmine in a TTS.

Preferably, in the use according to the invention amino group-free,hydroxyl group-free, and carboxyl group-free polyacrylates andpolyacrylate copolymers, such as acrylate-vinyl acetate copolymers areemployed.

In a particularly preferred embodiment of the use according to theinvention the acrylate-vinyl acetate copolymer Duro-Tak® 87-4098 isused.

In a further particularly preferred embodiment of the use according tothe invention the acrylate polymer Duro-Tak® 87-9088 is used.

A further aspect of the present invention is the use of polyisobutyleneand polybutene as exclusive constituents of the contactadhesive/adhesive enhancer in the adhesive layer of a TTS that issuitable for an application period of at least two or at least threedays. Here, according to the preceding aspects of the present inventionthe polyisobutylene and polybutene preferably are present as mixtures ofdifferent average molecular weights.

A further aspect of the present invention is to provide the TTSaccording to the invention for the treatment of the Alzheimer's diseaseand Parkinson's dementia. Here, the TTS according to the invention ispreferably prepared for an application period of at least two or atleast three days. Longer application periods are also possible.

In the following, preferred embodiments of the TTS according to theinvention are described with respect to experimental examples and theirproperties are determined in terms of the stability.

EXPLANATIONS OF THE FIGS. 1-7

In the following, parameter “n” indicates the number of repeats of themeasurements performed leading to averaged results.

FIG. 1: Schematic cross-section of a rivastigmine TTS with membrane (nottrue to scale).

FIG. 2: Graph regarding the maximum cold flow of the active substancelayers after 9 weeks of storage at 25° C./60% r.h. and 40° C./75% r.h.(n=2).

FIG. 3: Graph regarding the adhesiveness of the adhesive layers preparedaccording to the examples (n=3).

FIG. 4: In vitro permeation profile of rivastigmine from Exelon® (n=6).

FIG. 5: In vitro permeation profiles of rivastigmine from two-layerlaminates with and without membrane (n=4).

FIG. 6: In vitro permeation profiles of rivastigmine from two-layerlaminates with adhesive layers based on a polyacrylate adhesive (n=4).

FIG. 7: In vitro permeation profiles of rivastigmine from two-layerlaminates with different membranes and adhesive layers in comparison toExelon® (n≥4).

FIG. 8: In vitro permeation profiles of rivastigmine from two-layerlaminates with different membranes (n≥4).

FIG. 9: In vitro release profile of rivastigmine from two-layerlaminates with different membranes (n≥4).

EXAMPLES

The components used in the following formulation examples can bedescribed in more detail as follows:

TABLE 1 Summary of the components of the formulation examples ComponentDesignation Chemical Description Function Duro-Tak ® Acrylate/VinylAcetate Matrix Polymer 87-4098 Copolymer Duro-Tak ® Acrylate CopolymerMatrix Polymer 87-9088 Cab-O-Sil ® Pyrogenic Silica Gel-forming AgentOppanol ® B10 Polyisobutylene Contact Adhesive (M_(V) = ca. 4 ×10⁴g/mol) Oppanol ® B50 SF Polyisobutylene Contact Adhesive (M_(V) = ca.4 × 10⁵g/mol) Indopol H-100, Polybutene (M_(N) = 910, Tackifier H-1900,H-6.000, 2,500, 4,200 or 6,000 H-18.000 g/mol) Eudragit ® E100 AcrylateCopolymer Matrix Polymer

Example 1 Preparation of Different Active Substance Layer Formulations

Three different active substance layer formulations containingrivastigmine base have been prepared. A summary of the constituents ofthe different formulations is given in table 2.

TABLE 2 Active Substance Layers used Matrix Active Substance WeightCharge Layer (R) mg/10 cm² 010RIDTDS 40% Rivastigmine; 64 60% DT ®87-9088 011RIDTDS 40% Rivastigmine; 62 60% DT ® 87-4098 012RIDTDS 40%Rivastigmine; 54 60% Eudragit ® E100

In FIG. 2, the results on the physical stability (cold flow) of thepreceding reservoir formulations are given. The formulation with DT®87-9088 (010RIDTDS) after 9 weeks of storage shows the lowest cold flowand thus, is particularly suitable as a matrix-forming agent for theactive substance layer.

Example 2

Six different formulations of the adhesive layer have been prepared. Asummary of the constituents of the different formulations is given intable 3.

TABLE 3 Adhesive Layers used Matrix Layer Charge Adhesive Layer (A)mg/10 cm² 019RIDTDS 17.91% Oppanol ® B10 SFN; 30 31.84% Oppanol ® B50SF;29.85% Indopol ® H-100; 19.90% Indopol ® H-1900; 0.50% Cab-O-Sil ® M5P005RIDTDS 24.88% Oppanol ® B10 SFN; 32 24.88% Oppanol ® B50SF; 24.88%Indopol ® H-100; 24.88% Indopol ® H-1900; 0.50% Cab-O-Sil ® M5P013RIDTDS 24.88% Oppanol ® B10 SFN; 32 24.88% Oppanol ® B50SF; 24.88%Indopol ® H-100; 24.88% Indopol ® H-6000; 0.50% Cab-O-Sil ® M5P014RIDTDS 24.88% Oppanol ® B10 SFN; 30 24.88% Oppanol ® B50SF; 24.88%Indopol ® H-100; 24.88% Indopol ® H-18000; 0.50% Cab-O-Sil ® M5P015RIDTDS 29.85% Oppanol ® B10 SFN; 35 19.90% Oppanol ® B50SF; 19.90%Indopol ® H-1900; 29.85% Indopol ® H-18000; 0.50% Cab-O-Sil ® M5PC006RIVTDS 64.5% Oppanol ® B10 SFN/ 30 B50SF (4/6); 35.0% Paraffin; 0.5%Cabo-O-Sil ®

In FIG. 3, the results of measurements of the adhesiveness of theprepared adhesive layers are shown. These show that by the addition ofIndopol® to the Oppanol® adhesive the adhesiveness is significantlyimproved in comparison to the use of paraffin. Moreover, theadhesiveness can be further increased and controlled by the specificselection of the molecular weights of the polymers used.

Example 3

Finally, six different charges of TTS formulations have been prepared. Asummary of the composition of the different charges is made in table 4.

TABLE 4 Charges used: Active Substance Matrix Weight Charge Layer(R)Adhesive Layer (A) Membrane mg/10 cm² 015/017 40% Rivastigmine; 29.85%Oppanol ® B10SFN — 015RIDTDS RIDTDS 60% DT ® 87-9088 19.90% Oppanol ®B50SF (A): 35 without 19.90% Indopol ® H-1900 017RIDTDS Membrane 29.85%Indopol ® H-18000 (R): 60 0.50% Cap-O-Sil M5P 015/017 40% Rivastigmine;29.85% Oppanol ® B10SFN CoTran ™ 015RIDTDS RIDTDS 60% DT ® 87-908819.90% Oppanol ® B50SF 9719 (A): 35 CoTran 19.90% Indopol ® H-1900017RIDTDS 9719 28.85% Indopol ® H-18000 (R): 60 0.50% Cap-O-Sil M5P009/010 40% Rivastigmine; 10% Rivastigmine; Celgard ® 009RIDTDS RIDTDS60% DT ® 87-9088 90% DT ® 87-2516 2400 (A): 33 Celgard 010RIDTDS 2400(R): 64 009/010 40% Rivastigmine; 10% Rivastigmine; Solupor ® 009RIDTDSRIDTDS 60% DT ® 87-9088 90% DT ® 87-2516 10P05A (A): 33 Solupor010RIDTDS 10P05A (R): 64 029/030 40% Rivastigmine; 20% Oppanol ® B10 SFNSolupor ® 029RIDTDS RIDTDS 60% DT ® 87-9088 30% Oppanol ® B50SF 10P05A(A): 34 Solupor 30% Indopol ® H-100 030RIDTDS 10P05A 20% Indopol ®H-1900 (R): 61 028/030 40% Rivastigmine; 30% Oppanol ® B10 SFN CoTran ™028RIDTDS RIDTDS 60% DT ® 87-9088 20% Oppanol ® B50SF 9719 (A): 28CoTran 20% Indopol ® H-1900 030RIDTDS 9719 30% Indopol ® H-18000 (R): 61070/071 40% Rivastigmine; 30% Oppanol ® B10 SFN CoTran ™ 070RIDTDSRIDTDS 60% DT ® 87-9088 20% Oppanol ® B50SF 9720 (A): 30 CoTran 20%Indopol ® H-1900 071RIDTDS 9720 30% Indopol ® H-18000 (R): 60

Preparation Method 1. Preparation of the Active Substance Layer

The acrylate adhesive has been added first and rivastigmine and ethylacetate were weighted in. Subsequently, the components were mixed insufficient ethyl acetate by means of a stirrer such that a spreadablehomogeneous coating mass is formed.

The homogeneous coating mass was applied to a siliconized foil(“intermediate liner”) as a thin film. The matrix film was dried at 60°C./20 min and 80° C./5 min and subsequently backed with a cover layer ofPET.

Subsequently, the “intermediate liner” was pulled off and it was backedthe control membrane.

2. Preparation of the Adhesive Layer and the Overall Laminate

The polyisobutylene adhesives were weighted in together and mixed.Subsequently, heptane and Cab-O-Sil® were added with stirring andstirred until the mass was homogeneous.

The mass was applied to a pull-off layer (“release liner”) as a thinfilm and subsequently, the solvents were removed at 60° C./20 min and80° C./5 min. After drying, the laminate is backed with an activesubstance layer.

Patches of suitable size were punched from the obtained laminate.

3. In Vitro Mouse Skin Permeation Test

With the charges of table 4 and the commercial product Exelon® TDS, aone-day formulation, in vitro mouse skin permeation tests have beenperformed.

The results of these tests are given in FIGS. 4 to 7. FIG. 4 shows thepermeation profile of rivastigmine from the commercially availableExelon® TDS. The curve trace in FIG. 4 clearly shows that the deliveryrate of rivastigmine significantly decreases already after 24 hours.Thus, this system does not ensure the continuous and uniform activesubstance delivery over an application period of more than 24 hours.

FIG. 5 shows that a continuous and uniform active substance delivery forseveral days will only be permitted by the interposed membrane.

The formulation charges 009/010RIDTDS Celgard® 2400 and 009/010RIDTDSSolupor® 10P05A that contain polyacrylate as the matrix-forming agentfor the adhesive layer surprisingly had a similar kinetics compared withthat of Exelon® TDS (cf. FIGS. 4 and 6). This shows that polymers fromthe group of the polyacrylates and their copolymers are not suitable asmatrix-forming agent for the adhesive layer, since they do not ensure asufficient control of the active substance delivery over the applicationtime of several days even with an interposed membrane.

FIGS. 5 and 7 show that by the combination of a membrane controlling therelease of the active substance and an adhesive layer based on apolyisobutylene/polybutene mixture a control of the medicinal drugdelivery over a time interval of several days is permitted.

FIG. 8 shows that with the two formulations “C008RIDTDS” and “070/071RIDTDS CoTran 9720” a uniform linear permeation profile over seven daysis achieved. Thus, these formulations are particularly suitable as 5-daypatches, 6-day patches and 7-day patches. The formulation “C008RIDTDS”is derived from a clinical charge and has the same composition asformulation I (060/062RIDTDS_Cotran9719) described in example 4.

4. In Vitro Release

The in vitro release was determined with the “Disk assembly Method”according to Ph. Eur. 5.0 <2.9.4>.

FIG. 9 shows that both formulations “C008RIDTDS” and “070/071 RIDTDSCoTran 9720” exhibit a uniform release of the active substance over atleast seven days.

Example 4: Stability Test

According to the method mentioned above still two further formulationshave been prepared:

TABLE 5 Formulation 1 Formulation II (060/062RIDTDS_Cotran9719)(058/062RIDTDS_Cotran9728) Active Substance Layer Rivastigmine (40%)Rivastigmine (40%) 60 g/m² DT ® 87-9088 (60%) DT ® 87-9088 (60%)Membrane CoTran ™ 9719 CoTran ™ 9728 Adhesive Layer Oppanol ® B10 SFN(30%) Oppanol ® B10 SFN (30%) 30 g/m² Oppanol ® B50 SF (20%) Oppanol ®B50 SF (40%) Indopol ® H-1900 (20%) Indopol ® H-1900 (30%) Indopol ®H-18000 (30%)

The punched TTS were sealed in bags of aluminum composite foils and eachstored for at least one month at 25° C. and 60% relative air humidity,or at 40° C. and 75% relative air humidity, respectively. Subsequently,the content of optionally impurities formed as a consequence of thedecomposition of rivastigmine was determined by means of HPLC and UVabsorption.

The TTS according to the invention showed an excellent stability overseveral months. After storage, only very low amounts ofimpurities/decomposition products were identified, although the activesubstance layer did not contain any antioxidants. This was achieved bythe employment of a polymer matrix without hydroxyl groups and withoutcarboxyl groups.

The results are summarized in the following table 6:

Temperature Charge ° C./% r.h. Initial 1 Month 2 Months 3 Months Purity060/062RIDTDS 25/60 Imp. 1: 0.04% (<RL); Imp. 1: 0.05% (<RL); Imp. 1:0.02% (<RL); Imp. 1: 0.02% (<RL); n = 3 _CoTran9719 40/75 Imp. 4: 0.02%(<RL); Imp. 4: 0.06% (<RL); Imp. 4: 0.07% (<RL); RRT = 0.84: 0.01%(<RL); Imp. 5: 0.05% (<RL); Imp. 5: 0.14%; Imp. 5: 0.18%; Imp. 2: 0.02%(<RL); → Sum: 0.0% → Sum: 0.14% → Sum: 0.18% Imp. 4: 0.06% (<RL); Imp.1: 0.04% (<RL); Imp. 5: 0.17%; RRT = 0.85: 0.06% (<RL); → Sum: 0.17%Imp. 2: 0.02% (<RL); Imp. 4: 0.11%; Imp. 5: 0.23% (<RL); → Sum: 0.34%058/062RIDTDS 25/60 Imp. 1: 0.04% (<RL); Imp. 1: 0.05% (<RL); Imp.1:0.02% (<RL); Imp. 1: 0.02% (<RL); _CoTran9728 40/75 Imp. 4: 0.02% (<RL);Imp. 4: 0.05% (<RL); Imp. 4: 0.06% (<RL); RRT = 0.84: 0.02% (<RL); Imp.5: 0.05% (<RL); Imp. 5: 0.15%; Imp. 5: 0.18%; Imp. 2: 0.02% (<RL); →Sum: 0.0% → Sum: 0.15% → Sum: 0.18% Imp. 4: 0.09% (<RL); Imp. 1: 0.05%(<RL); Imp. 5: 0.18%; RRT = 0.85: 0.04% (<RL); → Sum: 0.18% Imp. 2:0.03% (<RL); Imp. 4: 0.09% (<RL); Imp. 5: 0.22%; → Sum: 0.22% RL =“Reporting Limit” (detection limit) RRT = relative retention time (HPLC)

1. A transdermal therapeutic system for administering an activesubstance through the skin, comprising the layers arranged in thefollowing order with respect to each other: a) a cover layer, b) anactive substance layer comprising a polymer matrix containing the activesubstance, c) an adhesive layer comprising (1) a polyisobutylene or amixture of several polyisobutylenes and (2) a polybutene or a mixture ofseveral polybutenes; and d) a pull-off layer, characterized in that theactive substance layer does not contain any free hydroxyl groups andfree carboxyl groups and the transdermal therapeutic system isconfigured to provide a substantially linear permeation profile of theactive substance over a period of at least 48 hours.
 2. The transdermaltherapeutic system according to claim 1, characterized in that theadhesive layer comprises at least two polyisobutylenes with differentaverage molecular weights and at least two polybutenes with differentaverage molecular weights.
 3. The transdermal therapeutic systemaccording to claim 2, characterized in that the first polyisobutylenepolymer has an average molecular weight M_(v) of about 40,000 g/mol andthe second polyisobutylene polymer has an average molecular weight M_(v)of about 400,000 g/mol.
 4. The transdermal therapeutic system accordingto claim 3, characterized in that the first polybutene polymer has anaverage molecular weight M_(n) in the range of 700-2,800 g/mol and thesecond polybutene polymer has an average molecular weight M_(n) in therange of 2,200-6,500 g/mol.
 5. The transdermal therapeutic systemaccording to claim 1, wherein the active substance layer contains 30-50%by weight of the active substance and 50-70% by weight of the polymermatrix, based on the total weight of the active substance layer.
 6. Thetransdermal therapeutic system according to claim 1, characterized inthat the polymer matrix of the active substance layer comprises at leastone polymer and/or copolymer without free hydroxyl groups and withoutfree carboxyl groups selected from the group consisting ofpolyacrylates, acrylate-vinyl acetate copolymers, polyisobutylene,styrene-butadiene copolymers, and mixtures thereof.
 7. The transdermaltherapeutic system according to claim 1, characterized in that it doesnot contain tocopherols.
 8. The transdermal therapeutic system accordingto claim 1, characterized in that it does not contain any antioxidantselected from the group consisting of tocopherols, butylatedhydroxyanisole, and butylated hydroxytoluene.
 9. The transdermaltherapeutic system according to claim 1, characterized in that it doesnot contain any antioxidant.
 10. The transdermal therapeutic systemaccording to claim 1, characterized in that it is suitable for theapplication over at least 2 days.
 11. The transdermal therapeutic systemaccording to claim 1, characterized in that it shows a substantiallylinear skin permeation of the active substance over a period of at least48 hours, as measured by an in vitro skin permeation test.
 12. A methodfor the preparation of a transdermal system according to claim 1comprising i) the preparation of a component containing the activesubstance layer that contains the cover layer and the active substancelayer, which is on the side of the cover layer that is supposed to bethe side facing the skin; ii) the preparation of a component containingthe adhesive layer that contains the pull-off layer and the adhesivelayer on the pull-off layer; iii) laminating onto each other thecomponents of i) and ii) such that the cover and pull-off layer in thecross-section of the finished TTS represent the opposing outermostlayers.
 13. The method according to claim 12 comprising i) applying andoptionally subsequent drying of a film of a composition forming theactive substance layer, optionally in the form of a solution ordispersion in a suitable medium, onto the side of the cover layersupposed to be the side facing the skin; ii) applying and optionallysubsequent drying of a film of a composition forming the adhesive layer,optionally in the form of a solution or dispersion in a suitable medium,onto the pull-off layer; and iii) laminating onto each other thecomponents of i) and ii) such that the cover and pull-off layer in thecross-section of the finished TTS represent the opposing outermostlayers;
 14. Method of treating Alzheimer's disease and Parkinson'sdementia by administrating the transdermal therapeutic system accordingto claim
 1. 15. The method for treating Alzheimer's disease andParkinson's dementia according to claim 14, characterized in that thetransdermal therapeutic system administered over a period of at least 48hours.
 16. A method for the stabilization of rivastigmine in a TTS,characterized in that rivastigmine, or a salt or solvate thereof, is (i)embedded in a polymer matrix having no free hydroxyl groups and no freecarboxyl groups, or (ii) introduced into an active substance layercontaining no free hydroxyl groups and no free carboxyl groups.
 17. Amethod for the reduction of the degradation of rivastigmine in a TTS,characterized in that rivastigmine, or a salt or solvate thereof, is (i)embedded in a polymer matrix having no free hydroxyl groups and no freecarboxyl groups, or (ii) introduced into an active substance layercontaining no free hydroxyl groups and no free carboxyl groups.
 18. Thetransdermal therapeutic system according to claim 2, characterized inthat the first polybutene polymer has an average molecular weight M_(n)in the range of 700-2,800 g/mol and the second polybutene polymer has anaverage molecular weight M_(n) in the range of 2,200-6,500 g/mol.